Novel Use of SelectfluorTM for the Synthesis of cis-Fused Pyrano- and Furanotetrahydroquinolines

Aryl imines formed in situ from aryl aldehydes and aromatic amines undergo smooth [4+2] cycloaddition reactions with cyclic enol ethers such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran in the presence of 10 mol % Selectfluor^TM in acetonitrile at room temperature to afford pyrano- and furanotetrahydroquinoline derivatives in excellent yields with high endo-selectivity.     

Synthesis of Multisubstituted Silyloxy-based Donor-Acceptor Cyclobutanes by an Acid-Catalyzed [2+2] Cycloaddition

This account summarizes our recent efforts on the acid-catalyzed [2+2] cycloaddition of silyl enol ethers with α,β-unsaturated esters, giving donor-acceptor (D -A) cyclobutanes and their related reactions. The cycloaddition generally produces multisubstituted cyclobutanes in good yields with high diastereoselectivity. We found that aluminum Lewis acids and triflic imide (Tf₂NH) had good catalytic activity. The retro [2+2] cycloaddition proceeded at higher reaction temperatures, and in some cases, diastereoselectivity switching of cycloadducts was observed. A microflow protocol was established for Tf₂NH-catalyzed [2+2] cycloaddition. Although the cycloaddition usually requires cryogenic conditions in a batch reactor, the microreactor system enabled the production of D -A cyclobutanes, even at ambient temperature. [2+2] Cycloaddition of allylsilanes and alkyl enol ethers, instead of silyl enol ethers, afforded the corresponding D -A cyclobutanes.     

Sulfines,a unique class of sulfur-centered heterocumulenes†

The chemistry of sulfines (thione S-oxides) is briefly reviewed with focus on highlights and milestones. Sulfines can conveniently be prepared by oxidation of a large variety of thiocarbonyl-containing compounds. Alkylidenation of sulfur dioxide with α -silyl carbanions is an attractive method of preparation as it allows access to sulfines that cannot be obtained by the oxidation method. The reaction of activated methylene compounds with thionyl chloride is a highly versatile method of preparation. The scope of the reaction with thionyl chloride is extended by using silyl enol ethers and silyl ketene acetals as starting materials.

The cycloaddition reaction of sulfines with 1,3-dienes is widely used for trapping purposes. The Diels–Alder type cycloadducts are useful compounds in synthesis. Dipolar cycloaddition reactions are of interest as well as the addition reaction of alkyllithium regents. O-Alkylation of aminosulfines gives iminosulfenates which are of interest for further synthetic elaboration.     

Dehydration of 2-(2-Arylethyl)-2-hydroxy-4-oxopentanoic Acids and their hydrazones to form heterocycles

Dehydration of 2-(2-arylethyl)-2-hydroxy-4-oxopentanoic acids 1 with hydrochloric acid/acetic acid, affords 3-(2-arylethyl)-5-hydroxy-5-methyl-2(5H)-furanones 4 . Compounds of type 1 and 4 represent suitable precursors for the formation of pyridazin-3-ones 7 as they smoothly react with hydrazine. A new series of s-triazolo[4,3-b]pyridazin-3-ones 12 and tetrazolo[1,5-b]pyridazines 15 are obtained from the 3-chloropyridazines 11 upon treatment with semicarbazide and sodium azide, respectively. Reaction of 11 with phenyl- acetyl-hydrazine provides 3-benzyl-6-phenyl-8-(2-phenyl-ethyl)-s-triazolo[4,3-b]pyridazine 13 via dehydrative cyclization of the intermediate 14 which was clarified to exhibit tautomeric equilibria between enol–hydrazine form A and keto–hydrazine form B by means of ¹H and ¹³C NMR spectroscopy. Attempts to synthesize 3-alloxy-pyridazines 18 by reacting 11 with sodium alloxide afford N-allyl compounds 17 .     

Elusive Dehydroalanine Derivatives with Enhanced Reactivity

For the first time, a simple methodology for the chemical synthesis and use of highly reactive 4-methylenoxazol-5(4H)-ones from serine is presented. These dehydroalanine derivatives, which resemble the natural 4-methylidenimidazole-5-one (MIO) cofactor present in lyases and aminomutases, undergo rapid reaction with carbon nucleophiles such as silyl enol ethers, as well as cycloaddition reactions with diazo compounds and reactive dienes, under very mild conditions and without any need for metal catalysts or ring-strain activation, offering potential for bioconjugation.     

Preparation of ‘click’ hydrogels from polyaspartamide derivatives

Lately, copper‐assisted azide–alkyne cycloaddition (CuAAC) has become a very interesting tool for synthesizing biocompatible polymer‐based materials such as hydrogels or microgels, which can be used as biomaterials for tissue engineering and drug delivery. Novel poly(2‐hydroxyethyl aspartamide)s (PHEAs) functionalized with pendent acetylene or azide groups were prepared from polysuccinimide, which is the thermal polycondensation product of aspartic acid, through successful ring‐opening reactions using propargylamine, 1‐azido‐2‐aminoethane and ethanolamine. The composition of the prepared copolymers was analyzed using ¹H NMR spectroscopy. Clickable PHEA derivatives were crosslinked by mixing together in water with a catalyst system of Cu(I) and N, N, N′, N′, N″‐pentamethyldiethylenetriamine, a type of Huisgen's 1,3‐dipolar azide‐alkyne cycloaddition. The reaction of the polymers resulted in a chemoselective coupling between alkynyl and azido functional groups with multiple formation of triazole crosslinks to give hydrogels. The triazole linkages in the hydrogels are highly stable and may also play a role in swelling behavior. PHEA‐based hydrogels were also obtained by the crosslinking of azide‐ or alkyne‐modified PHEA with a small‐molecule crosslinker. The hydrogels prepared using these two methods were characterized by their degree of swelling and the morphology of the hydrogels was confirmed using scanning electron microscopy. The approach we describe here presents a promising alternative to common chemical hydrogel preparation techniques, and these hydrogels seem to possess structures having potential for a variety of industrial and biomedical applications. © 2012 Society of Chemical Industry     

Ene Reactions and [2+2]Cycloadditions of Nitrilium Salts with Alkenes

N-Alkylnitrilium salts ( 1 ) undergo ene reactions with electron-rich di- and higher substituted alkenes 2 to afford either 2-azoniaallene salts ( 3, 6, 9, 11 ) (the nitrilium salt reacting as ene and the alkene reacting as enophile) or 1-azonia-1,4-pentadiene salts ( 10, 12 ) (the alkene reacting as ene and the nitrilium salt reacting as enophile). Competing with ene reactions tri- and tetrasubstituted alkenes and N-alkylnitrilium salts undergo [2+2]cycloaddition to furnish azetinium salts ( 8, 13 ). In solution, alkyl substituted 2-azoniaallene salts tautomerize to 2-azonia-1,3-butadiene salts ( 4, 5, 7 ). The constitutions of the 2-azoniaallene salt 6c and the azetinium salt 8 were secured by X-ray crystallographic analyses.     

Vilsmeier–Haack–Arnold formylations of aliphatic substrates with N-chloromethylene-N,N-dimethylammonium salts

The classical electrophilic substitution of activated aromatics with the Vilsmeier–Haack reagent N-chloromethylen-N,N-dimethylammonium chloride (Schemes 1 and 2) has been more recently extended to a great variety of aliphatic substrates, mainly due to the work of Arnold. In this review, a collection of representative examples for these henceforth called Vilsmeier–Haack–Arnold (VHA) formylation reaction of aliphatics is given: the reaction of polymethine cyanines, merocyanines, and other vinylogous iminium salts with the VHA reagent gives, after hydrolysis of the primary substitution products, trialdehydes such as triformylmethane (Scheme 3); VHA reaction with ene-diamines and diene-diamines yields N,N-dialkylaminomalonaldehydes and tetraaldehydes such as 1,1,2,2-tetraformylethane, respectively (Schemes 4 and 5); aldehyde acetals, enol ethers, and carboxylic acids deliver with VHA reagents 2-substituted malonaldehydes (Scheme 6), and α-amino acids give derivatives of the unstable aminomalonaldehyde (Scheme 7); alkenes and polyenes react with VHA reagents to give α,β-unsaturated or higher vinylogous aldehydes (Schemes 8 and 9), and alkenes with donor substituents yield alkylidene-malonaldehydes (Scheme 10); enolizable methyl and methylene ketones produce with VHA reagents 3-chlorovinylaldehydes (Scheme 11). Eventually, the VHA reagent can be used for the intermediate preparation of nucleophilic amino-chlorocarbenes (Scheme 12).     

Four‐Electron Electrocyclic Ring‐Opening/Intermolecular [4+2] Cycloadditions of α‐Hydroxycyclobutenones: Stereoselective Synthesis of Multiple Substituted δ‐Lactams

A four‐electron electrocyclic ring‐opening/intermolecular [4+2] cycloaddition of α‐hydroxycyclobutenones is reported. The reaction represents the first example for the intermolecular cycloaddition of the extensively studied enol‐ketene intermediate, and provides a new synthetic route to multiply substituted δ‐lactams in high stereoselectivity.

     

Synthesis of a glycosaminoglycan polymer mimetic using an N‐alkyl‐N,N‐linked urea oligomer containing glucose pendant groups

The synthesis of a glycosaminoglycan polymer mimetic is reported. An isopropylidene protected glucose methacrylate monomer was copolymerized under reversible addition fragmentation chain transfer polymerization control with an azido‐containing comonomer to a molecular weight of 29 000 g mol^?1 with polydispersity of 1.21. The comonomer ratio was determined to be 15:1 based on ¹H NMR spectroscopy. This copolymer was coupled to sugar‐functionalized N‐alkyl‐N,N‐linked urea oligomers using a copper catalyzed alkyne/azide cycloaddition reaction. The reaction efficiency was 100% as monitored by ¹H NMR spectroscopy. The isopropylidene protecting groups on the polymer and N‐alkyl‐N,N‐linked urea oligomers were removed using acid hydrolysis to give the final polysaccharide mimetic. It is expected that these polymers will have applications in a variety of future therapeutic applications. © 2013 Society of Chemical Industry     

Click‐coupling of anthraquinone dyes with β‐cyclodextrin: formation of polymeric superstructures

Two novel cyclodextrin‐modified anthraquinone dyes were synthesized and investigated for their complexation behaviour and formation of superstructures. Therefore, 1‐fluoro‐4‐N‐(propargylamino)anthraquinone and 1,4‐bis(propargyloxy)anthraquinone were prepared via nucleophilic aromatic displacement and subsequently covalently ‘click‐coupled’ in a copper(I)‐catalysed azide–alkyne cycloaddition with β‐cyclodextrin monoazide. Both the propargyl‐modified precursor and the click‐coupled anthraquinone dyes were evaluated as hosts and guests, respectively, in β‐cyclodextrin interactions. The anthraquinone dye bearing two cyclodextrins, 1,4‐bis((1‐β‐cyclodextrin‐1H‐1,2,3‐triazol‐5‐yl)methoxy)anthraquinone, enables the reversible formation of supramolecular crosslinked poly[(N,N‐dimethyl acrylamide)‐co‐(N‐(ferrocenoylmethyl)acrylamide)] ( 11 ), whereas the monofunctionalized compound 1‐fluoro‐4‐(((1‐β‐cyclodextrin‐1H‐1,2,3‐triazol‐5‐yl)methyl)amino)anthraquinone can be supramolecularly linked to 11 resulting in coloured polymers. These features of β‐cyclodextrin‐linked anthraquinone dyes can be verified with either ¹H ¹H NMR rotating frame nuclear Overhauser effect spectroscopy or the naked eye. © 2016 Society of Chemical Industry     

Zinc‐Catalyzed Tandem Diels–Alder Reactions of Enynals with Alkenes: Generation and Trapping of Cyclic o‐Quinodimethanes (o‐QDMs)

A systematic investigation of ZnCl₂‐catalyzed reactions of enynals with alkenes has been undertaken. Structurally unique propeller‐like products could be obtained under mild conditions. Cyclic o‐quinodimethanes (o‐QDMs) are generated through [4+2] cycloaddition between enynals and alkenes. Both electron‐poor and electron‐rich dienophiles could be used to trap the active intermediate through [4+2] cycloaddition. But [1,5]‐H shift products could also be observed when electron‐rich alkenes were used as dienophile. DFT calculations were performed to understand the reaction mechanism. A competition between the [4+2] cycloaddition and [1,5]‐H shift was proposed for the transformation of cyclic o‐QDMs. The selectivity could be affected by the properties of the substrates.

     

Efficient and Flexible Synthesis of Highly Functionalised 4‐Aminooxazoles by a Gold‐Catalysed Intermolecular Formal [3+2] Dipolar Cycloaddition

Oxazoles are important motifs within bioactive and functional materials. Complex, fully substituted and functionalised 4‐aminooxazoles are accessed by an efficient intermolecular reaction between an ynamide and an N‐acylpyridinium N‐aminide in the presence of a gold catalyst. The formal [3+2] dipolar cycloaddition employs a nucleophilic nitrenoid approach to access the 1,3‐N,O‐dipole character in a controllable fashion. The selectivity for a cycloaddition pathway provides a stark contrast against the indiscriminate reactivity of electrophilic acyl nitrenes. Protocols for the formation of acyl‐functionalised aminides are reported from accessible precursors including carboxylic esters and acids. The function of these aminides in the oxazole‐forming reaction has been explored and it is shown that substantial elaboration is accommodated despite proximity to the reactive centre. As a result functional oxazole‐based motifs, such as chiral oxazoles with biologically pertinent substitution patterns, are readily accessible. The use of ynamide types that are unexplored or little used in gold catalysis has been evaluated. Unusual all‐heteroatom substitution patterns around the oxazole are shown to be accessible using thio‐ynamides. The study shows that a close stoichiometry of reactants is suitable alongside relatively low loadings of the bench‐stable precatalysts in practically straightforward multi‐mmol scale reactions. The efficiency and flexibility of this regioselective intermolecular preparation is demonstrated in the ready synthesis of oxazoles with substantial structural and functional group variation.

     

Highly Selective Synthesis of a 2‐Deoxyxylonolactam via Enantioselective Carbon‐Hydrogen Insertion Reactions Using Chiral Dirhodium(II) Carboxamidates

N‐Benzyl‐2‐deoxyxylonolactams are accessible by highly chemoselective, diastereoselective, and enantioselective carbon‐hydrogen insertion reactions of diazoacetamides. Competing aromatic cycloaddition or β‐lactam formation via carbon‐hydrogen insertion into a benzylic position can be minimized by the proper selection of chiral catalyst. Conformational influences are important in product preference.     

N‐Imide Ylide‐Based Reactions: C?H Functionalization,Nucleophilic Addition and Cycloaddition

As valuable building blocks for introducing nitrogen, N‐imide ylides represent an important class of reactive species and are synthons for the synthesis of nitrogen‐containing heterocycles that potentially have biological activities. During the past decades, tremendous efforts have been devoted to the tandem processes involving N‐imide ylides as well as their asymmetric applications. In particular, several types of N‐imide ylide‐based reactions have been established, such as C H functionalization, nucleophilic addition, and cycloaddition, etc. In this review, recent advances in N‐imide ylides chemistry are presented ordered according to the sequence of various reaction types.

     

Das Reaktionsprodukt von Phenylalanin und Ninhydrin: Eine Strukturrevision. Protonentransfer in einem N-unsubstituierten,hochstabilisierten Azomethin-Ylid

The Reaction Product of Phenylalanin and Ninhydrin: Revision of Its Structure. Proton Transfer in an N-Unsubstituted, Highly Stabilized Azomethinylide The formerly proposed structures 6 and 7 for the intense colored reaction product of ninhydrin and phenylalanin are revised in favour of 5a , for which four other tautomeric forms 5b–5e have to be taken into account. Representing a highly stabilized N-unsubstituted azomethinylide 5a can be trapped with N-phenylmaleimide as dipolarophile; 1,3-dipolar cycloaddition and subsequent double bond shift leads to two diastereomeric products 15a and 15b . UV spectrometric data and dynamic ¹H NMR measurements reveal an intramolecular proton transfer by hydrogen bonding between 5a and 5b dominating the tautomeric equilibrium.     

Bis(nitrone) as crosslinking agent for unsaturated polyesters via 1,3‐dipolaric cycloaddition

The microwave‐assisted polycondensation of maleic anhydride and 1,6‐hexanediol was carried out using p‐toluenesulfonic acid as catalyst. The resulting unsaturated polyester was characterized using Fourier transform infrared (FTIR) and ¹H NMR spectroscopy, and the molecular weight determined using gel permeation chromatography. 4,4′‐Decanediyldioxydi(N‐methyl‐p‐phenylenenitrone) was chosen as a model compound for the crosslinking of the unsaturated polyester. The crosslinking, which is known to proceed via 1,3‐dipolaric cycloaddition, was followed using differential scanning calorimetry. Additionally, the kinetics of the cycloaddition was evaluated at 120 °C using FTIR spectroscopy. Copyright © 2012 Society of Chemical Industry     

Modular P?OP Ligands in Rhodium‐Mediated Asymmetric Hydrogenation: A Comparative Catalysis Study

Highly efficient and enantioselective hydrogenation reactions for α‐(acylamino)acrylates, itaconic acid derivatives and analogues, α‐substituted enol ester derivatives, and α‐arylenamides (25 substrates) catalyzed by chiral cationic rhodium complexes of a set of P OP ligands have been developed. The catalytic systems derived from these P OP ligands provided a straightforward access to enantiomerically enriched α‐amino acid, carboxylic acid, amine, and alcohol derivatives that are valuable chiral building blocks. Excellent efficiencies (full conversion in all cases) and extremely high enantiomeric excesses (94–99% ee) were achieved for a wide range of α‐substituted enol ester derivatives, regardless of the substitution pattern. The R‐oxy group of the ligand (methoxy or triphenylmethoxy) strongly influences the enantioselectivity and catalytic activity. Greater steric bulk around the metal centre correlated to greater (or similar) enantioselectivity, but also to slower hydrogenation. Furthermore, the hydrogenation rates observed with the four model substrates follow the same trend, independently of the R‐oxy group of the ligand: methyl 2‐acetamidoacrylate>dimethyl itaconate>1‐phenylvinyl acetate>N‐(1‐phenylvinyl)acetamide. A substrate‐to‐catalyst ratio (S/C) of up to 10,000:1 was sufficient for total hydrogenation of a model substrate of intermediate reactivity (dimethyl itaconate), and did not imply any loss in conversion or enantioselectivity.     

Copper‐Catalyzed N‐Alkylation of Sulfonamides with Benzylic Alcohols: Catalysis and Mechanistic Studies

The N‐alkylation of sulfonamides with alcohols is efficiently performed in the presence of easily available copper catalysts via hydrogen borrowing methodology. Applying a copper acetate/potassium carbonate system the reaction of sulfonamides and alcohols gave the corresponding secondary amines in excellent yield. In situ HR‐MS analysis indicated that bissulfonylated amines are formed under air atmosphere, which act as self‐stabilizing ligands for the catalytic system. UV‐visible measurements suggest the interaction between the copper centre and the bissulfonylated amine. Reactions of benzyl alcohol‐d₇ with p‐toluenesulfonamide, N‐benzyl‐p‐toluenesulfonamide or N‐benzylidenetoluenesulfonamide revealed that the reaction proceeds via a transfer hydrogenation mechanism and the whole process is micro‐reversible. Competitive reactions of benzyl alcohol and benzyl alcohol‐d₇ with p‐toluenesulfonamide revealed a kinetic isotope effect (kH/kD) of 3.287 (0.192) for the dehydrogenation of benzyl alcohol and 0.611 (0.033) for the hydrogenation of the N‐benzylidene‐p‐toluenesulfonamide intermediate, which suggests that dehydrogenation of the alcohol is the rate‐determining step.